In recently reported studies, p53 mutations were found in 50% of HCC patients in two geographic areas (China and South Africa) where both a high aflatoxin diet and chronic HBV infection are common, and it was suggested that the p53 mutations could have been due to exposure to aflatoxin. In reports from low-aflatoxin regions, p53 mutations have been reported in none to 19% of patients with HCC. Most of these studies did not closely examine the possible role of HBV. Hepatocellular carcinomas from 43 patients from a high-aflatoxin region of China and two low-aflatoxin regions in the USA were stained to detect mutant p53 protein. Mutant p53 was detected in the nuclei of hepatocellular carcinoma cells from 14/23 (61%) patients from China, and from 3/10 (30%) and 6/10 (60%) patients from the two regions in the USA, and was closely associated with detection of hepatitis B surface antigen (HBsAg) in hepatocytes of the adjacent nontumorous liver. Thus, mutations of the tumor suppressor gene p53 in hepatocellular carcinomas are not limited to geographic regions where the ingestion of aflatoxin is high and may be associated with hepatitis B virus infection. The detection of mutant p53 in the present study was closely associated with the detection of HBsAg in adjacent nontumorous hepatocytes. In a patient who had already sustained a mutation or deletion in one allele due to aflatoxin ingestion or other causes, HBV could cause a mutation in the second p53 allele or its protein products could interfere with the normal function of the second p53 allele. It is also possible that HBV could cause a dominant negative mutation in a single allele of p53 resulting in loss of tumor suppression, contributing to subsequent HCC.